Hemophilia Gene Therapy May Be Effective Long-Term

A single dose of adeno-associated virus (AAV)–mediated gene therapy resulted in sustained clinical benefit and no late-onset safety concerns throughout a 13-year follow-up in men with severe hemophilia B, according to results published June 11 in the New England Journal of Medicine. The study represents the longest reported follow-up for any gene therapy for hemophilia B.

Investigators from University College London and St Jude Children’s Research Hospital in Tennessee followed 10 adult men who received the gene therapy, scAAV2/8-LP1-hFIXco, between 2010 and 2012 at low, intermediate or high dose levels. Initial safety and effectiveness results were reported in 2014.

After a median follow-up of 13 years, mean factor IX expression remained stable across all dose groups: 1.7 IU per deciliter in the low-dose group, 2.3 IU per deciliter in the intermediate-dose group and 4.8 IU per deciliter in the high-dose group. Seven participants no longer required prophylactic treatment, and the median annualized bleeding rate dropped from 14.0 to 1.5 episodes. The use of factor IX concentrate decreased by a factor of 12.4.

Fifteen vector-related adverse events occurred during the study, including transient elevations in liver aminotransferase levels (of grade 1 or 2) in four of six patients in the high-dose group, but this was managed by steroid administration. Two participants developed cancers during the follow-up period, though a multidisciplinary review suggested that both were likely unrelated to gene therapy.

Notably, the therapy did not appear to have any toxic effects. A liver biopsy performed 10 years after infusion showed sustained transgene expression without signs of necrosis, fibrosis or dysplasia. According to investigators, the results point to a significant quality-of-life improvement for the treated individuals.

“It’s incredibly rewarding to see the sustained safety and efficacy, which truly validates the potential of gene therapy as a one-time treatment for this condition,” said chief investigator Amit Nathwani, PhD, from UCL Cancer Institute and London’s Royal Free Hospital. “Our findings answer critical questions about the long-term durability of gene therapy, offering profound hope and a significantly improved quality of life for patients.”